The origin of the Church of the Holy Cross is linked to the establishment of the homonymous Confraternity in 1318. In the following centuries this gothic building was renovated and expanded. The renovation of the oratory in the fifteenth century gave it its current appearance. In the second half of the following century, the facade was enriched with painted decorations by Giorgio Picchi.

Noteworthy are the ceiling with decorative friezes and figures as well as the front of the Holy Thorn chapel with the statues of David and Jonah by P. Lanci. By the same author are also stucco and statues which well demonstrate the taste of the time. In the church you can admire two frescoes of the fifteenth-century, a San Sebastiano in half figure by Giovanni Santi, painted around 1475, and a Madonna and Child and Angels by Ottaviano Nelli.

The Confraternity enjoyed a privileged protection of both the Church and the Dukes of Urbino, in particular of Federico da Montefeltro, who commissioned a bronze relief depicting the Deposition from the Cross by Francesco di Giorgio Martini, removed during the Napoleonic period and now conserved in Venice in the church of S. Maria del Carmine.